ACP InternistWeekly

In the News for the Week of March 19, 2013

Highlights

Internal medicine residency match results encouraging

The number of U.S. senior medical students choosing categorical internal medicine residencies increased this year for the
fourth consecutive year, according to the 2013 National Resident Matching Program. More...

Chlorthalidone does not lead to fewer cardiovascular events and deaths than hydrochlorothiazide but may be more likely to
cause electrolyte imbalances, especially hypokalemia, according to a new study. More...

Test yourself

MKSAP Quiz: following chemotherapy in the hospital

A 51-year-old man is being followed in the hospital after receiving chemotherapy for acute myeloid leukemia 1 day ago. Kidney
function was normal at the start of his treatment, which consisted of normal saline at a rate of 200 mL/h and rasburicase
on the day of chemotherapy. Following a physical exam and lab results, what is the most appropriate next step in management? More...

High-value care

Magnetic resonance imaging (MRI) performed as a one-year follow-up in patients who had been treated for sciatica and lumbar-disk
herniation did not distinguish patients with persistent or recurrent symptoms of sciatica from asymptomatic patients, a study
found. More...

Five excuses physicians and patients should question

Yul Ejnes, MD, MACP, immediate past chair of ACP's Board of Regents and a member of ACP Internist's editorial board, continues his column at KevinMD.com on five commonly used excuses for not implementing recommendations
for high-value care. More...

Sleep apnea

Patients with sleep apnea had comparable outcomes after treatment in primary and specialty care, indicating that primary care
physicians may be able to effectively treat the condition, a new study reports. More...

FDA update

Warning on irregular heart rhythms with azithromycin

Azithromycin (Zithromax or Zmax) can cause abnormal changes in the electrical activity of the heart that may lead to a potentially
fatal irregular heart rhythm, the FDA warned last week. More...

Cartoon caption contest

Put words in our mouth

ACP InternistWeekly wants readers to create captions for our new cartoon and help choose the winner. Pen the winning caption and win a $50 gift
certificate good toward any ACP product, program or service. More...

Physician editor: Philip Masters, MD, FACP

Highlights

Internal medicine residency match results encouraging

The number of U.S. senior medical students choosing categorical internal medicine residencies increased this year for the
fourth consecutive year. According to the 2013 National Resident Matching Program, 3,135 U.S. medical school seniors matched
for residency training in internal medicine, a 6.6% increase compared to 2012, when 2,941 matched in internal medicine.

The report also showed a continued increase of U.S. medical graduates who matched in internal medicine-primary care (200 in
2013, 186 in 2012, and 166 in 2011) and in med-peds (increased to 312 in 2013, up from 276 in 2012).

"We are pleased that more U.S. medical students are choosing internal medicine residencies and hope the upward trend continues,"
said Steven Weinberger, MD, FACP, ACP's executive vice president and CEO. "However, ACP remains concerned about the need to
increase the nation's general internal medicine physician workforce to meet the needs of an aging population requiring care
for chronic and complex illnesses and the increased number of individuals who will be receiving coverage through the Affordable
Care Act."

Dr. Weinberger also cited problematic payment models and the exorbitant cost of medical education with the resulting financial
burden on medical students and residents as barriers to a career in general internal medicine.

The 2013 match for internal medicine is still well below the 3,884 U.S. medical school graduates that chose internal medicine
residency programs in 1985.

Categorical internal medicine enrollment numbers decreased from 2007 to 2009 (2,680 in 2007; 2,660 in 2008; and 2,632 in 2009)
before increasing to 2,772 in 2010 and 2,940 in 2011. The great majority of current internal medicine residents will ultimately
enter a subspecialty of internal medicine, such as cardiology or gastroenterology. Only about 20% to 25% of internal medicine
residents eventually choose to specialize in general internal medicine, compared with 54% in 1998.

Chlorthalidone does not lead to fewer cardiovascular events and deaths than hydrochlorothiazide but may be more likely to
cause electrolyte imbalances, especially hypokalemia, according to a new study.

Researchers in Canada performed a propensity score-matched observational cohort study to compare the safety and effectiveness
of chlorthalidone and hydrochlorothiazide in older adults with hypertension. Patients who were at least 66 years of age, began
treatment with either drug between Jan. 1, 1993, and March 31, 2010, and had not been hospitalized for heart failure, stroke
or myocardial infarction in the previous year were included. Each patient taking chlorthalidone was matched with at least
two patients taking hydrochlorothiazide by age, sex, year in which treatment began, and propensity score (a statistical indicator
that accounts for other differences between the matched patients that might bias the results of the comparison).

The study's primary outcome measure was death or hospitalization for heart failure, stroke or myocardial infarction. Hospitalization
with hypokalemia or hyponatremia was included as a safety outcome. Results appeared in the March 19 Annals of Internal Medicine.

Overall, 29,873 patients were included in the study, 10,384 receiving chlorthalidone and 19,489 receiving hydrochlorothiazide.
Over five years of follow-up, the primary outcome occurred at a rate of 3.2 events per 100 person-years of follow-up in the
chlorthalidone group and 3.4 events per 100 person-years of follow-up in the hydrochlorothiazide group (adjusted hazard ratio,
0.93 [95% CI, 0.81 to 1.06]). Hospitalization with hypokalemia and hyponatremia was more common in the chlorthalidone group
(adjusted hazard ratios, 3.06 [95% CI, 2.04 to 4.58] and 1.68 [95% CI, 1.24 to 2.28], respectively). The authors performed
nine post hoc analyses to compare patients taking 12.5, 25 or 50 mg of each of the drugs per day and found that the chlorthalidone
group had a higher risk for hospitalization in all six of the comparisons that yielded a statistically significant difference.

The authors noted that sample size or differences in patients' characteristics or physicians' treatment approaches may have
affected the study's ability to detect small differences in the two drugs' effectiveness. However, they concluded that with
typical use, chlorthalidone in older patients yielded similar adverse cardiovascular events and deaths compared with hydrochlorothiazide,
but was associated with higher rates of electrolyte abnormalities, notably hypokalemia.

In the absence of a larger randomized trial, they wrote, "it may be reasonable to conclude that hydrochlorothiazide is safer
than chlorthalidone in elderly patients at typically prescribed doses."

Test yourself

MKSAP Quiz: following chemotherapy in the hospital

A 51-year-old man is being followed in the hospital after receiving chemotherapy for acute myeloid leukemia 1 day ago. Kidney
function was normal at the start of his treatment, which consisted of normal saline at a rate of 200 mL/h and rasburicase
on the day of chemotherapy. He reports no symptoms except for some fatigue and nausea. He has no shortness of breath or fever.

On physical examination, the patient is afebrile. Blood pressure is 122/70 mm Hg, pulse rate is 72/min, and respiration rate
is 12/min. BMI is 25. Some bruising is noted on the skin. There is no jugular venous distention. Heart rate is regular. Lungs
are clear to auscultation. There is no edema.

Urine output has been around 50 mL/h.

Laboratory studies:

Albumin

3.2 g/dL (32 g/L)

Blood urea nitrogen

14 mg/dL (5.0 mmol/L)

Calcium

9 mg/dL (2.3 mmol/L)

Serum creatinine

1.0 mg/dL (88.4 µmol/L) (baseline: 0.9 mg/dL [79.6 µmol/L])

Electrolytes

Sodium

139 mEq/L (139 mmol/L)

Potassium

5.2 mEq/L (5.2 mmol/L)

Chloride

100 mEq/L (100 mmol/L)

Bicarbonate

25 mEq/L (25 mmol/L)

Phosphorus

5.7 mg/dL (1.84 mmol/L)

Uric acid

7.1 mg/dL (0.42 mmol/L)

Which of the following is the most appropriate next step in management?

High-value care

Magnetic resonance imaging (MRI) performed as a one-year follow-up in patients who had been treated for sciatica and lumbar-disk
herniation did not distinguish patients with persistent or recurrent symptoms of sciatica from asymptomatic patients, a study
found.

Researchers studied 267 patients from the Sciatica Trial, a nine-center, randomized trial of patients with a history of six
to 12 weeks of sciatica. In the study, patients were randomized to either surgery or prolonged conservative therapy, with
44% of the study group ultimately being treated surgically. Outcomes were evaluated by intention-to-treat analysis.

All patients underwent a follow-up MRI one year after randomization, which was interpreted for evidence of disc herniation
based on standard criteria by experienced neuroradiologists blinded to the clinical outcome. Patient outcomes were assessed
using a 7-point Likert scale for global perceived recovery, with a favorable clinical outcome defined as complete or nearly
complete disappearance of symptoms at one year.

At one year, disk herniation was visible in 35% of the patients with a favorable outcome (no symptoms) and in 33% of those
with an unfavorable outcome (95% CI for difference in proportion, −18.8 to 12.6; P=0.70). Nerve-root compression was present in 24% of the patients with a favorable outcome and in 26% of the patients with
an unfavorable outcome. Similar results were seen in patients with and without persistent leg and back pain at one year, as
well as those who would be considered more or less disabled based on responses to the Roland Disability Questionnaire.

The absence of disk herniation on follow-up MRI was not associated with a favorable outcome at one year (odds ratio, 0.82;
95% CI, 0.40 to 1.71; P=0.60), nor was the absence of MRI-assessed nerve-root compression (odds ratio, 1.03; 95% CI, 0.48 to 2.25; P=0.93). The size of the disk herniation (odds ratio, 1.48; 95% CI, 0.43 to 5.01; P=0.53) or the herniation form (protrusion vs. extrusion) (odds ratio, 0.88; 95% CI, 0.25 to 3.16; P=0.85) on follow-up MRI also had no association with a favorable clinical outcome.

The researchers wrote, "[P]atients asking for reimaging because of persistent or recurrent symptoms should be informed about
the difficulty in MRI interpretation after a first episode of acute sciatica. A recent systematic review concluded that even
in the acute setting of sciatica, evidence for the diagnostic accuracy of MRI is not conclusive."

Five excuses physicians and patients should question

Yul Ejnes, MD, MACP, immediate past chair of ACP's Board of Regents, a practicing internist in Cranston, R.I., and a member
of ACP Internist's editorial board, continues his column at KevinMD.com, one of the Web's leading destinations for provocative physician commentary.
In this month's post, Dr. Ejnes critiques five commonly used excuses for not implementing recommendations for high-value care.

Cardiology

Darbepoetin alfa did not improve clinical outcomes in patients with systolic heart failure and mild to moderate anemia, a
study found.

Researchers conducted a double-blind trial that randomly assigned 2,278 patients with systolic heart failure and mild to moderate
anemia (hemoglobin level, 9.0 to 12.0 g/dL) to receive either darbepoetin to a hemoglobin target of 13 g/dL or placebo. Primary
clinical outcomes were death from any cause or first hospitalization for worsening heart failure. Secondary outcomes included
the Summary Score and Symptom Frequency Score on the Kansas City Cardiomyopathy Questionnaire. These scores are based on a
100-point scale with higher scores indicating a better quality of life and fewer symptoms; a change of 5 points is considered
clinically meaningful. The study was published early online March 10 by New England Journal of Medicine.

The primary composite outcome of death from any cause or first hospitalization for worsening heart failure occurred in 576
patients (50.7%) in the darbepoetin group and 565 (49.5%) in the placebo group (hazard ratio [HR] in the darbepoetin group,
1.01; 95% CI, 0.90 to 1.13; P=0.87). Results were similar when adjusted for baseline characteristics (adjusted HR, 1.01; 95% CI, 0.90 to 1.13; P=0.88), in the as-treated analysis (HR, 0.98; 95% CI, 0.86 to 1.13; P=0.82) and across all subgroups examined.

There were 474 deaths (41.7%) in the darbepoetin group and 458 (40.1%) in the placebo group (HR, 1.04; 95% CI, 0.92 to 1.19; P=0.51), for annualized mortality rates of 14.4% and 13.8%, respectively. There were similar rates of death from cardiovascular
causes, of first hospitalization for worsening heart failure, and on each component of the composite outcome. Five hundred
seventy-two hospitalizations for heart failure (including second and subsequent hospitalizations) occurred in the darbepoetin
group and 695 occurred in the placebo group (P=0.06 from a negative binomial model).

An improvement in the Overall Summary Score on the Kansas City Cardiomyopathy Questionnaire of 5 points or more at six months
was seen in 53% of the darbepoetin group and 48% of the placebo group (P=0.06). Increases from baseline to six months in the Symptom Frequency Score were 6.20 points (95% CI, 4.71 to 7.69 points)
in the darbepoetin group and 3.91 points (95% CI, 2.42 to 5.40 points) in the placebo group (P=0.01).

There were similar adverse event rates for the drug compared to placebo. Embolic and thrombotic adverse events were reported
in 153 patients (13.5%) in the darbepoetin group and 114 (10.0%) in the placebo group (P=0.01). Septic shock was reported significantly more frequently in the darbepoetin group than in the placebo group, although
there was no excess of other serious adverse events related to infection in the darbepoetin group. Stroke and cancer rates
did not significantly differ between treatment and control groups, and there was no significant between-group difference in
systolic blood pressure during the study.

The researchers wrote, "[O]ur findings suggest that the hemoglobin level, like other surrogates, is simply a marker of poor
prognosis in heart failure rather than a therapeutic target."

Sleep apnea

Patients with sleep apnea had comparable outcomes after treatment in primary and specialty care, indicating that primary care
physicians may be able to effectively treat the condition, a new study reports.

Researchers in Australia performed a randomized, controlled, noninferiority study to compare the clinical efficacy of diagnosing
and caring for sleep apnea using a simplified model in primary care and in specialist sleep centers. The study's primary outcome
was change in Epworth Sleepiness Scale (ESS) score over six months; the scale ranges from a score of 0, or no daytime sleepiness,
to 24, or high daytime sleepiness.

The study also examined disease-specific and general quality-of-life measures, symptoms of obstructive sleep apnea, adherence
to continuous positive airway pressure, patient satisfaction and health care costs. Results appeared in the March 13 Journal of the American Medical Association.

Between September 2008 and June 2010, patients were assigned to treatment at primary care practices (n=81) or at a sleep medicine center at a university hospital (n=74). Most of the patients (81.3%) were men, with a mean age of 57.2 years in the primary care group and 54.5 years in the
specialty care group. Mean body mass index was 33.1 kg/m2 in the primary care group and 33.7 kg/m2 in the specialty care group; patients with a body mass index higher than 50 kg/m2 were excluded. The treatment plans at both types of locations included positive airway pressure, mandibular advancement splints
or conservative measures.

Over six months, patients in the primary and specialty care groups showed significant improvement in ESS score compared with
baseline (mean decrease, 12.8 points to 7.0 points vs. 12.5 points to 7.0 points; P<0.001 for both comparisons). Management in primary care was found to be noninferior to management in specialty care
(mean change in ESS score, 5.8 to 5.4; adjusted difference, −0.13; P=0.43). Secondary outcomes did not differ between the groups, but a larger proportion of patients withdrew from the study
in the primary care group than in the specialty care group (21% vs. 8%).

The authors acknowledged that their results may not be generalizable to all patients with sleep apnea and that they could
not determine why more patients from the primary care group withdrew from the study, among other limitations. However, they
concluded that their results indicated noninferiority between primary and specialty care for sleep apnea.

"With adequate training of primary care physicians and practice nurses and with appropriate funding models to support an ambulatory
strategy, primary care management of obstructive sleep apnea has the potential to improve patient access to sleep services,"
the authors wrote.

They cautioned that their study results should not be extrapolated to settings where primary care physicians "may not be as
skilled and motivated as those who participated in this randomized controlled trial and in which patient outcomes may not
be as good as those observed in this study." They also called for more research into the cost-effectiveness of a primary care
approach.

FDA update

Warning on irregular heart rhythms with azithromycin

Azithromycin (Zithromax or Zmax) can cause abnormal changes in the electrical activity of the heart that may lead to a potentially
fatal irregular heart rhythm, the FDA warned last week.

The warning was based on an FDA review of a study released last spring, which found higher risk of cardiovascular death in patients on azithromycin therapy compared to those taking no antibiotics,
as well as new data from the manufacturer. Patients at particular risk for these adverse effects include those with known
risk factors such as existing QT interval prolongation, low blood levels of potassium or magnesium, a slower-than-normal heart
rate, or use of certain drugs used to treat arrhythmias.

The FDA recommends that clinicians consider the risk of torsades de pointes and fatal heart rhythms with azithromycin when
choosing treatments for patients who are already at risk for cardiovascular events. The potential risk of QT prolongation
with azithromycin should be placed in appropriate context when choosing an antibacterial drug. Alternative drugs in the macrolide
class, or non-macrolides such as the fluoroquinolones, also have the potential for QT prolongation or other significant side
effects, according to an agency press release.

Cartoon caption contest

Put words in our mouth

ACP InternistWeekly wants readers to create captions for this cartoon and help choose the winner. Pen the winning caption and win a $50 gift certificate
good toward any ACP product, program or service.

E‑mail all entries to acpinternist@acponline.org. ACP staff will choose finalists and post them online for an online vote by readers. The winner will appear in an upcoming
edition.

MKSAP Answer and Critique

The correct answer is C: Increase intravenous saline rate. This item is available to MKSAP 16 subscribers as item 3 in the
Nephrology section.

MKSAP 16 released Part A on July 31, 2012, and Part B was released on Feb. 1, 2013. More information is available online.

An increase in the intravenous saline rate is appropriate. This patient with acute myeloid leukemia received chemotherapy
1 day ago and is at risk for tumor lysis syndrome. Manifestations include acute kidney injury and arrhythmias resulting from
the release of potassium, phosphorus, and uric acid from cells. The cell death can be spontaneous with highly proliferative
malignancies but more commonly is induced by chemotherapy. Patients with untreated tumor lysis syndrome present with hyperkalemia,
hyperuricemia, and hyperphosphatemia. Optimal treatment to prevent tumor lysis syndrome is intravenous fluids to promote a
faster urine flow rate. The goal intravenous fluid rate is up to 3000 mL/m2/d, around 6 L/d in this patient. Although his initial intravenous fluid rate was reasonable, his high phosphorus and potassium
levels suggest that cell breakdown is occurring, and an increased rate of saline infusion will help promote potassium excretion
and decrease the solubility of phosphorus and uric acid by increasing urine volume. In this patient, an increased intravenous
fluid with normal saline at a rate of 250 mL/h would be appropriate. The use of a loop diuretic to maintain urine flow is
also reasonable in selected patients.

Although intravenous fluid with sodium bicarbonate has the benefit of alkalinizing the urine and therefore increasing uric
acid clearance, it also increases the risk of calcium phosphorus precipitation, which can increase damage to the kidneys,
and is not appropriate for this patient with a high serum phosphorus level.

Sodium polystyrene sulfonate can be used to treat this patient's hyperkalemia but will not improve his urine flow.

Rasburicase is generally preferred to allopurinol for prophylaxis of tumor lysis syndrome because of differences in mechanism.
Rasburicase directly breaks down uric acid and minimizes xanthine accumulation, whereas allopurinol does not. Because this
patient's serum uric acid levels appear to be adequately controlled with rasburicase, there would be no benefit of treatment
with allopurinol.

Test yourself

A 66-year-old man is evaluated for a persistent rash for 6 years' duration. The rash waxes and wanes in severity, and it becomes pruritic only after he becomes hot and sweating, such as when he mows the lawn or exercises. It has always been limited to his back and lower chest. He has never treated it. The patient is otherwise well, has no other medical problems, and takes no medication. Following a physical exam, what is the most likely diagnosis?

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